title: Combined linkage and association analyses identify a novel locus for obesity near PROX1 in Asians.
abstract: OBJECTIVE
  Although genome-wide association studies (GWAS) have substantially contributed to understanding the genetic architecture, unidentified variants for complex traits remain an issue. One of the efficient approaches is the improvement of the power of GWAS scan by weighting P values with prior linkage signals. Our objective was to identify the novel candidates for obesity in Asian populations by using genemapping strategies that combine linkage and association analyses.
  
  
  METHODS
  To obtain linkage information for body mass index (BMI) and waist circumference (WC), we performed a multipoint genome-wide linkage study in an isolated Mongolian sample of 1,049 individuals from 74 families. Next, a family-based GWAS, which integrates within- and between-family components, was performed using the genotype data of 756 individuals of the Mongolian sample, and P values for association were weighted using linkage information obtained previously.
  
  
  RESULTS
  For both BMI (LOD = 3.3) and WC (LOD = 2.6), the highest linkage peak was discovered at chromosome 10q11.22. In family-based GWAS combined with linkage information, six single-nucleotide polymorphisms (SNPs) for BMI and five SNPs for WC reached a significant level of association (linkage weighted P < 1 × 10(-5) ). Of these, only one of the SNPs associated with WC (rs1704198) was replicated in 327 Korean families comprising 1,301 individuals. This SNP was located in the proximity of the prosperorelated homeobox 1 (PROX1) gene, the function of which was validated previously in a mouse model.
  
  
  CONCLUSIONS
  Our powerful strategic analysis enabled the discovery of a novel candidate gene, PROX1, associated with WC in an Asian population.
authors.affiliation: Genomic Medicine Institute (GMI), Medical Research Center, Seoul National University, Seoul, Republic of Korea; Department of Biomedical Sciences, Seoul National University Graduate School, Seoul, Republic of Korea.
authors.forename: Hyun-Jin
authors.initials: HJ
authors.lastname: Kim
authors.forename: Yun Joo
authors.initials: YJ
authors.lastname: Yoo
authors.forename: Young Seok
authors.initials: YS
authors.lastname: Ju
authors.forename: Seungbok
authors.initials: S
authors.lastname: Lee
authors.forename: Sung-Il
authors.initials: SI
authors.lastname: Cho
authors.forename: Joohon
authors.initials: J
authors.lastname: Sung
authors.forename: Jong-Il
authors.initials: JI
authors.lastname: Kim
authors.forename: Jeong-Sun
authors.initials: JS
authors.lastname: Seo
mesh_terms: D000293:Adolescent; D000328:Adult; D044466:Asian People / Q000235:genetics / Q000706:statistics & numerical data; D015992:Body Mass Index; D005260:Female; D008040:Genetic Linkage; D056426:Genetic Loci; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D018398:Homeodomain Proteins / Q000235:genetics*; D006801:Humans; D008297:Male; D008875:Middle Aged; D009765:Obesity / Q000208:ethnology / Q000235:genetics*; D025521:Tumor Suppressor Proteins / Q000235:genetics*; D055105:Waist Circumference; D055815:Young Adult; D000098551:Prospero-Related Homeobox 1 Protein
chemical_list: D018398:Homeodomain Proteins; D025521:Tumor Suppressor Proteins; D000098551:Prospero-Related Homeobox 1 Protein